This proposal is in response to RFA Biological Effects of Chemical Interactions, and deals with potential synergistic teratogenic interactions caused by combination of chemical dump and environmental chemicals. EPA has identified 200 chemicals in the Love Canal dump, some of which are known teratogens. We chose three for study: acetaldehyde, phthalates, and salicylates (aspirin), and also caffeine which is ingested in beverages, etc. and is a known, mild teratogen. In recently completed animal studies we found that caffeine, when coadministered with several other teratogens, greatly potentiated the incidence and severity of birth defects caused by them. We have also conducted an extensive study of the interactions of a wide variety of teratogens including inhibitors of DNA, RNA, and protein synthesis, as well as caffeine and salicylates, and found combinations of any two agents invariably resulted in synergistic potentiation of teratogenesis. This appears to be the general case, and can be anticipated with chemical dump and environmental teratogens also. We propose to determine the levels of these four agents which will produce full, minimal, and subteratogenesis in Wistar rats, and then conduct teratology tests with combinations of the agents at low levels to determine if in fact they interact synergistically. Those which do will be further studied with histological methods which provide a sensitive test for embryonic damage, possibly at low levels typical of human exposure. We propose also to elucidate mechanisms of synergistic teratogenic interactions, involving pharmacological, cytological, and biochemical studies. A hypothesis to be investigated is that synergistic teratogenesis is due to multifactorial insults to proliferating embryo cells, beyond their ability to repair damaged tissues. Another hypothesis to be tested is that safe antioxidants such as glutathione may protect against interacting chemical teratogens. The total study may aid in assessing the hazard of, and protecting against environmental and chemical dump teratogens.